Coatings for drug delivery devices based on poly (orthoesters)

ABSTRACT

A polymer coating for implantable medical devices based on polyorthoesters and methods for fabricating the coating are disclosed. The implantable medical devices made of polyorthoesters and methods for fabricating thereof are also disclosed.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is directed to coatings for implantable medical devices,such as drug eluting vascular stents.

2. Description of the State of the Art

Percutaneous transluminal coronary angioplasty (PTCA) is a procedure fortreating heart disease. A catheter assembly having a balloon portion isintroduced percutaneously into the cardiovascular system of a patientvia the brachial or femoral artery. The catheter assembly is advancedthrough the coronary vasculature until the balloon portion is positionedacross the occlusive lesion. Once in position across the lesion, theballoon is inflated to a predetermined size to radially compress againstthe atherosclerotic plaque of the lesion to remodel the lumen wall. Theballoon is then deflated to a smaller profile to allow the catheter tobe withdrawn from the patient's vasculature.

Problems associated with the above procedures includes formation ofintimal flaps or torn arterial linings which can collapse and occludethe conduit after the balloon is deflated. Moreover, thrombosis andrestenosis of the artery may develop over several months after theprocedure, which may require another angioplasty procedure or a surgicalby-pass operation. To reduce the partial or total occlusion of theartery by the collapse of arterial lining and to reduce the chance ofthe development of thrombosis and restenosis, a stent is implanted inthe lumen to maintain vascular patency.

Stents are used not only as a mechanical intervention but also as avehicle for providing biological therapy. As a mechanical intervention,stents act as scaffoldings, functioning to physically hold open and, ifdesired, to expand the wall of the passageway. Typically, stents arecapable of being compressed, so that they can be inserted through smallvessels via catheters, and then expanded to a larger diameter once theyare at the desired location. Examples in patent literature disclosingstents which have been applied in PTCA procedures include stentsillustrated in U.S. Pat. No. 4,733,665 issued to Palmaz, U.S. Pat. No.4,800,882 issued to Gianturco, and U.S. Pat. No. 4,886,062 issued toWiktor.

Biological therapy can be achieved by medicating the stents. Medicatedstents provide for the local administration of a therapeutic substanceat the diseased site. In order to provide an efficacious concentrationto the treated site, systemic administration of such medication oftenproduces adverse or toxic side effects for the patient. Local deliveryis a preferred method of treatment in that smaller total levels ofmedication are administered in comparison to systemic dosages, but areconcentrated at a specific site. Local delivery thus produces fewer sideeffects and achieves more favorable results. One proposed method formedicating stents involves the use of a polymeric carrier coated ontothe surface of a stent. A solution which includes a solvent, a polymerdissolved in the solvent, and a therapeutic substance dispersed in theblend is applied to the stent. The solvent is allowed to evaporate,leaving on the stent surface a coating of the polymer and thetherapeutic substance impregnated in the polymer. Once the stent hasbeen implanted at the treatment site, the therapeutic substance has asustained release profile from the polymer.

Local administration of therapeutic agents via stents has shown somefavorable results in reducing restenosis. However, the biologicalcompatibility of stent coatings or stents can be improved. For example,the ability of the surface of the stent coating to repel proteins can beimproved. A surface that does not adsorb proteins, or that adsorbs onlya minimal amount of proteins, is herein referred to as a “non-fouling”surface.

Accordingly, there is a need to have stent coatings with improvedbiological compatibility. The embodiments of the present invention aredirected to polymers and combination of polymers that satisfy this need.

SUMMARY

According to one embodiment of this invention, a coating for medicaldevices is provided. The coating comprises a polymer that is a productof co-polycondensation of a diketene acetal, a hydroxylated functionalcompound and a diol. The diketene acetal can be3,9-diethylidene-2,4,8,10-tetraoxaspiro-[5,5]-undecane;3,9-dipentylidene-2,4,8,10-tetraoxaspiro-[5,5]-heptadecane; or mixturesthereof. The hydroxylated functional compound can be poly(alkyleneglycols), hydroxylated poly(vinyl pyrrolidone), dextran, dextrin,hyaluronic acid, derivatives of hyaluronic acid, poly(2-hydroxyethylmethacrylate), or mixtures thereof. Diols can be alkylene glycols,oligoalkylene glycols, cycloaliphatic diols, or mixtures thereof.

According to another embodiment of the present invention, the coatingcomprises a polymer having the formula

wherein:

-   -   R and R₁ are each, independently, an unsubstituted or        substituted straight-chained, branched, or cyclic, C₁-C₈ alkyl        radical, or unsubstituted or substituted aryl radical;    -   R₂ is the repeating unit of the moiety providing the polymer        with non-fouling characteristics;    -   R₃ is an aliphatic or cycloaliphatic group;    -   m, n, p, and q are all integers, where the value of m is from 5        to 500, the value of n is from 2 to 350, the value of p is from        1 to 20, and the value of q is from 10 to 550.

According to yet another embodiment of the present invention, a methodfor fabricating a polymer coating for a medical device is provided. Themethod comprises applying a polymer onto the surface of the device,wherein the polymer comprises a product of co-polycondensation of adiketene acetal, a hydroxylated functional compound and a diol.

According to another embodiment of the present invention, an implantablemedical device is disclosed. The implantable medical device is made of apolymer comprising a product of co-polycondensation of a diketeneacetal, a hydroxylated functional compound and a diol.

DETAILED DESCRIPTION

A coating for an implantable medical device, such as a stent, accordingto one embodiment of the present invention, can include an optionalprimer layer, a drug-polymer layer (also referred to as “reservoir” or“reservoir layer”) or a polymer-free drug layer, and an optional topcoatlayer. The drug-polymer layer serves as a reservoir for the drug. Thereservoir layer or the polymer-free drug layer can be applied directlyonto the stent surface. The optional primer layer can be applied on thestent surface to improve the adhesion of the drug-polymer layer or thepolymer-free drug layer to the stent. The optional topcoat layer, whichcan be essentially free from any drugs, serves as a rate limitingmembrane that helps to control the rate of release of the drug.

According to the present invention, polyorthoesters are polymers thatcan be used to make any or all of the optional primer layer, thereservoir layer, and/or the optional topcoat layer. To obtainpolyorthoesters that are suitable for making stent coatings, at leastone compound of Group I is reacted with at least one compound of GroupII and at least one compound of Group III. Groups I, II, and III aredescribed below.

Group I. Diketene Acetals

Ketenes are compounds having carbonyl bond and carbon-carbon double bondadjacent each other and can be generally described by theformula >C═C═O. Diketenes, consequently, are compounds comprising twoketene groups. Diketene acetals include two reactive centers capable ofreacting with two hydroxy functional molecules to serve as a linkingagent. Diketene acetals have a general formula (I)

where R and R₁ can be, independently, unsubstituted or substitutedstraight-chained, branched, or cyclic, C₁-C₈ alkyl radicals, orunsubstituted or substituted aryl radicals. Any suitable substitutent asselected by those having ordinary skill in the art can be present in thesubstituted radicals.

Examples of suitable diketene acetals described by formula (I) that canbe used include 3,9-diethylidene-2,4,8,10-tetraoxaspiro-[5,5]-undecane(DETOSU), 3,9-dipentylidene-2,4,8,10-tetraoxaspiro-[5,5]-heptadecane(DPTOSH), 3,9-dibutylidene-2,4,8,10-tetraoxaspiro-[5,5]-pentadecane,3,9-dipropylidene-2,4,8,10-tetraoxaspiro-[5,5]-tridecane and mixturesthereof. Those having ordinary skill in the art can synthesize diketeneacetals, as described in the literature, for example, in Heller J., Adv.Polymer Sci., vol. 107, pp. 41-92 (1993).

Formula (I) describes the molecule of DETOSU where both R and R₁ aremethyl groups. Consequently, DETOSU has the formula (II):

For DPTOSH, both R and R₁ are n-butyl groups.

Group II. Hydroxy Functional Compounds

Group II comprises hydroxylated compounds having non-foulingcharacteristics. The hydroxylated compounds can react with the diketeneacetal to form soft segments of polyorthoesters. The soft segments canhave a glass transition temperature (T_(g)) below body temperature,e.g., for humans, below about 37° C. The hydroxyl group can be locatedin a terminal or non-terminal position of the molecule. Examples ofsuitable hydroxy functional compounds include poly(alkylene glycols),for example, poly(ethylene glycol) (PEG), poly(propylene glycol) (PPG)or poly(tetramethylene glycol), PLURONIC surfactants, hydroxylatedpoly(vinyl pyrrolidone), dextran, dextrin, hyaluronic acid and itsderivatives such as sodium hyaluronate, and poly(2-hydroxyethylmethacrylate), or mixtures thereof. PLURONIC is a trade name ofpoly(ethylene oxide-co-propylene oxide) and is available from BASF Corp.of Parsippany, N.J.

The molecular weight of a suitable compound of Group II can be such soas to allow passage of the released molecule through the kidneys, forexample, below 40,000 Daltons, such as between about 300 and 20,000Daltons.

Compounds of Group II can be described by the general formula (III):

where “m” is an integer, and —R₂—O— represents the moiety of compound(III) providing non-fouling characteristics. For example, when compound(III) is a poly(alkylene glycol), R₂ is the polymethylene structure(CH₂)_(x), where “x” is an integer. To illustrate for compound (III)being PEG, x=2.

Group III. Diols

Group III comprises short-to-moderate-length aliphatic or cycloaliphaticdiols or blends or combinations thereof. The diols can react with thediketene acetal to form hard segments of polyorthoesters. The hardsegments can either have some crystallinity or have a T_(g) above bodytemperature, e.g., about 37° C. The hard segments can serve as quasicross-linking agents both strengthening the final polyorthoester andenabling the polyorthoester to behave as an elastomer. Examples ofsuitable diols include alkylene glycols, for example, C₂ through C₁₆α,ω-glycols such as ethylene glycol (C₂), propylene glycol (C₃),butane-1,4-diol (C₄), pentane-1,5-diol (C₅), hexane-1,6-diol (C₆),heptane-1,7-diol (C₇), octane-1,8-diol (C₈), nonane-1,9-diol (C₉),decane-1,10-diol (C₁₀), undecane-1,11-diol (C₁₁), dodecane-1,12-diol(C₁₂), tridecane-1,13-diol (C₁₃), tetradecane-1,14-diol (C₁₄),pentadecane-1,15-diol (C₁₅), hexadecane-1,16-diol (C₁₆), or mixturesthereof, or other alkylene glycols, for example, butane-1,3-diol,pentane-2,4-diol, hexane-2,5-diol, or mixtures thereof. Other aliphaticdiols that can be used include oligoalkylene glycols such as diethyleneglycol, trimethylene glycol, tetramethylene glycol, tetraethyleneglycol, poly(tetraethylene glycol), poly(propylene glycol), and mixturesthereof. Examples of suitable cycloaliphatic diols includetrans-cyclohexanedimethanol, 1,4-cyclohexanediol, and mixtures thereof.

Compounds of Group III can be described by the general formula (IV):

where R₃ represents an aliphatic or cycloaliphatic group. For example,when compound (IV) is an alkylene glycol, R₃ is the poly- oroligomethylene structure (CH₂)_(y), where “y” is an integer from 2 to16. To illustrate, when compound (IV) is ethylene glycol, y=2. In caseof propylene glycol, y=3.

According to embodiments of the present invention, one way of preparingpolyorthoesters is to use a two-step synthetic process. The first stepincludes reacting the whole amount of diketene acetal of Group I with ahydroxy functional compound of Group II. The reaction (“reaction 1”) canbe conducted in an anhydrous environment at an elevated temperature, forexample, about 80° C., and can be catalyzed by a strong acid or base,e.g., p-toluenesulfonic acid. The second step includes adding a diol ofGroup III to the product of reaction 1, which can be conducted at anelevated temperature, for example, about 80° C. As a result of thetwo-step process described above, a polyorthoester can be obtained, thepolyorthoester having the general formula (V):

where R, R₁, R₂, and R₃ are as described above; m, n, p, and q are allintegers, where the value of m is from about 5 to about 500, the valueof n is from about 2 to about 350, the value of p is from about 1 toabout 20, and the value of q is from about 10 to about 550. Thepolyorthoester described by formula (V) can have molecular weight withina range of from about 20,000 to about 200,000 Daltons.

Polyorthoesters of this invention can be used for making stent coatings.The coating can be applied onto the stent by a commonly used methodknown to one of ordinary skill in the art, for instance, by spraying,dipping or molding. The polyorthoesters can be used to fabricate aprimer layer, a reservoir layer or a topcoat layer. The polyorthoesterscan be used alone or in combination with other suitable polymers.Poly(ethylene-co-vinyl alcohol) (EVAL) is one example of a polymer thancan be employed. EVAL is a product of hydrolysis of ethylene-vinylacetate copolymers and may also be a terpolymer including up to 5 molar% of units derived from styrene, propylene and other suitableunsaturated monomers. EVAL is available from Sigma-Aldrich Co. ofMilwaukee, Wis.

Representative examples of other suitable polymers includepoly(hydroxyvalerate), poly(L-lactic acid), polycaprolactone,poly(lactide-co-glycolide), poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester,polyanhydride, poly(glycolic acid), poly(D,L-lactic acid), poly(glycolicacid-co-trimethylene carbonate), polyphosphoester, polyphosphoesterurethane; poly(amino acids), cyanoacrylates, poly(trimethylenecarbonate), poly(iminocarbonate), co-poly(ether-esters) (e.g. PEO/PLA),polyalkylene oxalates, polyphosphazenes, biomolecules (such as fibrin,fibrinogen, cellulose, starch, collagen and hyaluronic acid),polyurethanes, silicones, polyesters, polyolefins, polyisobutylene andethylene-alphaolefin copolymers, acrylic polymers and copolymers, vinylhalide polymers and copolymers (such as polyvinyl chloride), polyvinylethers (such as polyvinyl methyl ether), polyvinylidene halides (such aspolyvinylidene fluoride and polyvinylidene chloride), polyacrylonitrile,polyvinyl ketones, polyvinyl aromatics (such as polystyrene), polyvinylesters (such as polyvinyl acetate), copolymers of vinyl monomers witheach other and olefins (such as ethylene-methyl methacrylate copolymers,acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl acetatecopolymers), polyamides (such as Nylon 66 and polycaprolactam), alkydresins, other polycarbonates, polyoxymethylenes, polyimides, polyethers,epoxy resins, other polyurethanes, rayon, rayon-triacetate, cellulose,cellulose acetate, cellulose butyrate, cellulose acetate butyrate,cellophane, cellulose nitrate, cellulose propionate, cellulose ethers,soluble fluorinated polymers and carboxymethyl cellulose.

The drug can include any substance capable of exerting a therapeutic orprophylactic effect for a patient. The drug may include small moleculedrugs, peptides, proteins, oligonucleotides, and the like. The drugcould be designed, for example, to inhibit the activity of vascularsmooth muscle cells. It can be directed at inhibiting abnormal orinappropriate migration and/or proliferation of smooth muscle cells toinhibit restenosis.

Examples of drugs include antiproliferative substances such asactinomycin D, or derivatives and analogs thereof (manufactured bySigma-Aldrich, or COSMEGEN available from Merck). Synonyms ofactinomycin D include dactinomycin, actinomycin IV, actinomycin I₁,actinomycin X₁, and actinomycin C₁. The active agent can also fall underthe genus of antineoplastic, anti-inflammatory, antiplatelet,anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic,antiallergic and antioxidant substances. Examples of suchantineoplastics and/or antimitotics include paclitaxel (e.g. TAXOL® byBristol-Myers Squibb Co., Stamford, Conn.), docetaxel (e.g. Taxotere®,from Aventis S. A., Frankfurt, Germany) methotrexate, azathioprine,vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g.Adriamycin® from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g.Mutamycin® from Bristol-Myers Squibb Co., Stamford, Conn.). Examples ofsuch antiplatelets, anticoagulants, antifibrin, and antithrombinsinclude sodium heparin, low molecular weight heparins, heparinoids,hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist antibody, recombinant hirudin, and thrombininhibitors such as Angiomax™ (Biogen, Inc., Cambridge, Mass.). Examplesof such cytostatic or antiproliferative agents include angiopeptin,angiotensin converting enzyme inhibitors such as captopril (e.g.Capoten® and Capozide® from Bristol-Myers Squibb Co., Stamford, Conn.),cilazapril or lisinopril (e.g. Prinivil® and Prinzide® from Merck & Co.,Inc., Whitehouse Station, N.J.); calcium channel blockers (such asnifedipine), colchicine, fibroblast growth factor (FGF) antagonists,fish oil (omega 3-fatty acid), histamine antagonists, lovastatin (aninhibitor of HMG-CoA reductase, a cholesterol lowering drug, brand nameMevacor® from Merck & Co., Inc., Whitehouse Station, N.J.), monoclonalantibodies (such as those specific for Platelet-Derived Growth Factor(PDGF) receptors), nitroprusside, phosphodiesterase inhibitors,prostaglandin inhibitors, suramin, serotonin blockers, steroids,thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist), andnitric oxide. An example of an antiallergic agent is permirolastpotassium. Other therapeutic substances or agents which may beappropriate include alpha-interferon, genetically engineered epithelialcells, tacrolimus, dexamethasone, and rapamycin and structuralderivatives or functional analogs thereof, such as40-O-(2-hydroxy)ethyl-rapamycin (known by the trade name of EVEROLIMUSavailable from Novartis), 40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin.

The stent, or other implantable medical device can be used in any partof the vascular system, including neurological, carotid, coronary,renal, aortic, iliac, femoral or any other part of the peripheralvasculature. The are no limitations on the size of the stent, itslength, diameter, strut thickness or pattern. Examples of suchimplantable devices include self-expandable stents, balloon-expandablestents, stent-grafts, grafts (e.g., aortic grafts). The coating can alsobe used with artificial heart valves, cerebrospinal fluid shunts,coronary shunts, pacemaker electrodes, and endocardial leads (e.g.,FINELINE and ENDOTAK, available from Guidant Corporation). Theunderlying structure of the device can be of virtually any design. Thedevice can be made of a metallic material or an alloy such as, but notlimited to, cobalt chromium alloy (ELGILOY), stainless steel (316L),“MP35N,” “MP20N,” ELASTINITE (Nitinol), tantalum, nickel-titanium alloy,platinum-iridium alloy, gold, magnesium, or combinations thereof.“MP35N” and “MP20N” are trade names for alloys of cobalt, nickel,chromium and molybdenum available from standard Press Steel Co.,Jenkintown, Pa. “MP35N” consists of 35% cobalt, 35% nickel, 20%chromium, and 10% molybdenum. “MP20N” consists of 50% cobalt, 20%nickel, 20% chromium, and 10% molybdenum. Devices made frombioabsorbable or biostable polymers could also be used with theembodiments of the present invention.

According to an embodiment of the present invention, the entire stentcan be made of a poly(ortho ester). Such stent is expected to becompletely biologically degradable and biologically absorbable. Forexample, the poly(ortho ester) stent can be gradually hydrolyzed as aresult of its contact with blood followed by absorption by the body.

A drug, for example, EVEROLIMUS can be optionally incorporated into thepoly(ortho ester) stent by mixing the drug with poly(ortho ester)followed by forming the stent out of the drug-poly(ortho ester) mixture.Alternatively, the drug can be applied on the surface of the poly(orthoester) stent after the poly(ortho ester) stent has been formed. To applythe drug on the surface of the poly(ortho ester) stent, the drug-polymersolution can be prepared, the solution containing the drug andpoly(ortho ester) in a mass ratio of about 1:3. The solution can beapplied onto the surface of the poly(ortho ester) stent followed bydrying.

The following examples demonstrate some embodiments of the presentinvention.

EXAMPLE 1 Synthesis of Poly(ethyleneglycol)-co-3,9-diethylidene-2,4,8,10-tetraoxaspiro-[5,5]-undecane-co-propyleneglycol (PEG-DETOSU-PG)

About 25 g (12.5 mmol) of PEG having a molecular weight (M_(w)) of about1,000 can be placed into a 1-liter round bottom flask equipped with amechanical stirrer. PEG can be treated to remove water by being heatedto about 80° C. using an oil bath, while being stirred under vacuum ofabout 25 mm Hg. About 400 g of tetrahydrofuran (THF) and about 27.83 g(131 mmol) of DETOSU can be added to the flask and dissolved withcontinued stirring. A solution of p-toluenesulfonic acid in THF havingconcentration of about 25 g/l can be prepared and about 15 drops of thissolution can be added to the contents of the flask. The stirring cancontinue for about 1 hour while the contents of the flask are maintainedat about 80° C. About 8.08 g (106 mmol) of propylene glycol can then beadded to the flask, and the stirring can be continued for about 1 morehour while the contents of the flask are kept at about 80° C. Thereaction mixture then can be cooled and about 1 liter of hexane can beadded. As a result, the polyorthoester PEG-DETOSU-PG, can be collectedby filtration. The polymer can then be purified by dissolution in drymethanol and precipitation with hexane. The ratio between the soft andhard segments in the polymer is about 1:1 by mass.

EXAMPLE 2 Synthesis of Poly(ethyleneglycol)-co-3,9-diethylidene-2,4,8,10-tetraoxaspiro-[5,5]-undecane-co-1,4-butanediol(PEG-DETOSU-BD)

About 25 g (12.5 mmol) of PEG having a M_(w) of about 2,000 can betreated to remove water as described in Example 1. About 400 g of THFand about 27.83 g (131 mmol) of DETOSU can be added to the flask anddissolved with continued stirring. About 10 drops of the solution ofp-toluenesulfonic acid described in Example 1 can be added to thecontents of the flask. The stirring can continue for about 1 hour whilethe contents of the flask are maintained at about 80° C. About 8.53 g(16.67 mmol) of 1,4-butanediol can then be added to the flask, and thestirring can continue for about 1 more hour while the contents of theflask are kept at about 80° C. The reaction mixture can then be cooledand about 1 liter of hexane can be added. As a result, thepolyorthoester PEG-DETOSU-BD, can be collected by filtration. Thepolymer can then be purified as described in Example 1. The ratiobetween the soft and hard segments in the polymer is about 7:3 by mass.Compared to PEG-DETOSU-PG described in Example 1, PEG-DETOSU-BD isexpected to be softer, more hydrophilic, more swellable in water, and isexpected to biodegrade faster.

EXAMPLE 3 Synthesis of Poly(ethyleneglycol)-co-3,9-dipentylidene-2,4,8,10-tetraoxaspiro-[5,5]-heptadecane-co-1,6-hexanediol(PEG-DPTOSH-HD)

About 25 g (83.3 mmol) of PEG having a M_(w) of about 300 can be treatedto remove water as described in Example 1. About 400 g of THF and about59.47 g (200.9 mmol) of DPTOSH can be added to the flask and dissolvedwith continued stirring. About 20 drops of the solution ofp-toluenesulfonic acid described in Example 1 can be added to thecontents of the flask. The stirring can continue for about 1 hour whilethe contents of the flask are maintained at about 80° C. About 14.21 g(122.5 mmol) of 1,6-hexanediol can then be added to the flask, and thestirring can continue for about 1 more hour while the contents of theflask are kept at about 80° C. The reaction mixture can then be cooledand about 1 liter of hexane can be added. As a result, thepolyorthoester PEG-DPTOSH-HD, can be collected by filtration. Thepolymer can then be purified as described in Example 1. The ratiobetween the soft and hard segments in the polymer is about 1:1 by mass.Compared to PEG-DETOSU-PG described in Example 1, PEG-DPTOSH-HD has morehydrophobic diketene acetal and shorter PEG chains. Consequently,PEG-DPTOSH-HD is expected to be harder, more hydrophobic, adsorb lesswater, and is expected to biodegrade more slowly.

Structure of the polyorthoesters of Examples 1-3 described by formula(V) can be summarized as shown in Table 1.

TABLE 1 Structure Polyorthoesters of Examples 1-3

No. Polyorthoester R R₁ R₂ R₃ m*⁾ n*⁾ p*⁾ q*⁾ 1 PEG-DETOSU-PG CH₃ CH₃(CH₂)₂ (CH₂)₃ 22 25 1 106 2 PEG-DETOSU-BD CH₃ CH₃ (CH₂)₂ (CH₂)₄ 45 13 117 3 PEG-DPTOSH-HD n-C₄H₉ n-C₄H₉ (CH₂)₂ (CH₂)₆ 6 83 1 123 *⁾The valuesof m, n, p, and q are rounded to the nearest integer

EXAMPLE 4

A first composition can be prepared by mixing the following components:

(a) about 2.0 mass % of poly(caprolactone); and

(b) the balance, a blend of the solvents THF and xylene at a mass ratioof THF to xylene of about 3:1.

The first composition can be applied onto the surface of a bare 12 mmTETRA stent by spraying and dried to form a primer layer. An EFD sprayhead can be used, having a 0.014 inch round nozzle tip and a 0.028 inchround air cap with a feed pressure of about 0.2 atm (3 psi) and anatomization pressure of between about 1 atm and 1.3 atm (15 to 20 psi).The total amount of solids of the primer layer can be about 40micrograms (μg). After spraying, the stents can be baked at about 55° C.for about one hour. “Solids” means the amount of dry residue depositedon the stent after all volatile organic compounds (e.g. the solvent)have been removed.

A second composition can be prepared by mixing the following components:

(a) about 2 mass % of poly(D,L-lactide);

(b) about 1 mass % of EVEROLIMUS; and

(c) the balance, a solvent blend of acetone and trichloroethane at amass ratio of about 1:1.

The second composition can be applied onto the dried primer to form areservoir layer, using the same spraying technique and equipment usedfor applying the primer layer. Solvent can be removed by baking at about50° C. for about one hour. The total amount of solids of thedrug-polymer layer can be about 320 μg.

A third composition can be prepared by mixing the following components:

(a) about 2 mass % of PEG-DETOSU-BD obtained as described in Example 2;

(b) the balance, a solvent blend of acetone and cyclohexanone at a massratio of about 1:1.

The third composition can be applied onto the dried reservoir layer toform a topcoat layer. Solvent can be removed by baking at 50° C. for onehour. The total amount of solids of the topcoat layer can be about 100μg.

EXAMPLE 5

A poly(ortho ester) can be synthesized of DETOSU and a diol component.The diol component can comprise a mixture of trans-cyclohexanediol and1,6-hexanediol in the molar ratio between trans-cyclohexanediol and1,6-hexanediol being about 7:3. Synthesis as described in Example 1 canbe used. The poly(ortho ester) can be dissolved in a blend oftrichloroethane and tetrahydrofuran solvents having about 1:1 mass ratiobetween the solvents. The concentration of the poly(ortho ester)solution can be about 6% by mass. EVEROLIMUS can then be added to thepoly(ortho ester) solution to form a drug-polymer solution. The massratio between EVEROLIMUS and poly(ortho ester) in the drug-polymersolution can be about 1:9.

A TEFLON rod having a diameter of about 3 mm can be dip coated with thepoly(ortho ester) solution, in an automated fashion, using dip coatingtechniques and equipment known to those having ordinary skill in theart. Between dips, the rod can be dried at about 40° C. for about 1minute. After a wall thickness of about 0.2 mm has been obtained, all ofthe solvent can be removed by baking in a vacuum oven overnight atambient temperature.

The polymer tube can be slipped off the TEFLON rod and a MULTI-LINKstent pattern can be cut into the polymer tube using a laser cutter. Thelaser cutter can include an eximer laser and CNC mechanism to positionthe stent under the laser. The stent pattern can be cut out in aconfiguration corresponding to the fully expanded state. Theself-expanding polymer stent can be then physically compressed andloaded onto a delivery catheter equipped with a guidewire lumen andretractable sleeve for deployment of the stent. Using standardpercutaneous techniques, this delivery catheter can be used to deliverand deploy the stent to stenosed vasculature where an ultimate size ofapproximately 3 mm is desired.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

1. A coating for a medical device comprising: a block copolymer having afirst block comprising a soft segment having a Tg below 37° C. whereinthe soft segment is a reaction product of a spirodiketene acetal and anon-fouling moiety selected from the group consisting of a poly(alkyleneglycol), poly(ethylene oxide-co-propylene oxide) (PLURONIC®),hydroxylated poly(vinyl pyrrolidone), dextran, dextrin, hyaluronic acidand derivatives thereof, poly(2-hydroxyethyl methacrylate) and mixturesthereof; and, a second block comprising a hard segment having a Tg above37° C. wherein the hard segment is a reaction product of a spirodiketeneacetal and a C₂-C₁₆ alkylene glycol, a cycloaliphatic diol, acyclohexanedimethanol, and an oligoaliphatic diol selected from thegroup consisting of diethylene glycol, triethylene glycol ortetraethylene glycol.
 2. A coating for a medical device wherein thecoating comprises a polymer having the formula

wherein R and R₁, are each independently a straight-chained, branched orcyclic alkyl radical C₁-C₈, or an aryl radical; R₂ is selected from thegroup consisting of methylene (—CH₂—), poly(alkylene glycol), poly(vinylpyrrolidone), dextran, dextrin, hyaluronic acid, derivatives ofhyaluronic acid, poly(2-hydroxyethyl methacrylate), or mixtures thereof;R₃ is an aliphatic group; m, n, p, and q are all integers, where thevalue of m is between 5 and 500, the value of n is between 2 and 350,the value of p is 1, and the value of q is between 10 and 550; and, the“n” block has a Tg less than 37° C. and the “q” block has a Tg above 37°C.
 3. The coating of claim 2, wherein R₂ is methylene (—CH₂—).
 4. Thecoating of claim 2, wherein R₂ is selected from the group consisting ofpoly(alkylene glycol), poly(vinyl pyrrolidone), dextran, dextrin,hyaluronic acid, and poly(2-hydroxyethyl methacrylate).
 5. The coatingof claim 1 wherein the spirodiketene acetal is3,9-dipentylidene-2,4,8,10-tetraoxaspiro-[5,5]-heptadecane (DPTOSH). 6.The coating of claim 1 wherein the medical device is a stent.
 7. Thecoating of claim 1 wherein the non-fouling moiety is selected from thegroup consisting of poly(ethylene glycol), poly(propylene glycol),poly(tetramethylene glycol), hydroxylated poly(vinyl pyrrolidone),dextran, dextrin, hyaluronic acid and poly(2-hydroxyethyl methacrylate).8. The coating of claim 1 wherein the alkylene glycol is selected fromthe group consisting of ethylene glycol, propylene glycol,butane-1,4-diol, pentane-1,5-diol, hexane-1,6-diol, heptane-1,7-diol,octane-1,8-diol, nonane-1,9-diol, decane-1,10-diol, undecane-1,11-diol,dodecane-1,12-diol, tridecane-1,13-diol, tetradecane-1,14-diol,pentadecane-1,15-diol, hexadecane-1,16-diol, butane-1,3-diol,pentane-2,5-diol and hexane-2,5-diol.
 9. The coating of claim 1 whereinthe spirodiketene acetal has the formula

wherein R and R₁ are independently selected from the group consisting ofstraight-chained, branched, or cyclic alkyl radicals C₁-C₈, and arylradicals.
 10. The coating of claim 9 wherein the spirodiketene acetal isselected from the group consisting of3,9-diethylidene-2,4,8,10-tetraoxaspiro-[5,5]-undecane,3,9-dipentylidene-2,4,8,10-tetraoxaspiro-[5,5]-heptadecane,3,9-dibutylidene-2,4,8,10-tetraoxaspiro-[5,5]-pentadecane and3,9-dipropylidene-2,4,8,10-tetraoxaspiro-[5,5]-tridecane.
 11. Thecoating of claim 9 wherein the alkylene glycol is selected from thegroup consisting of ethylene glycol, propylene glycol, butane-1,4-diol,pentane-1,5-diol, hexane-1,6-diol, heptane-1,7-diol, octane-1,8-diol,nonane-1,9-diol, decane-1,10-diol, undecane-1,11-diol,dodecane-1,12-diol, tridecane-1,13-diol, tetradecane-1,14-diol,pentadecane-1,15-diol, hexadecane-1,16-diol, butane-1,3-diol,pentane-2,4-diol and hexane-2,5-diol.